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Gastrointestinal System > Glycolysis and TCA Cycle - Abali 2/26/16 > Flashcards

Glycolysis and TCA Cycle - Abali 2/26/16 Flashcards

1
Q

glycolysis overview

A
  • breakdown of glucose to get energy (ATP)
  • conducted by all tissues

all cells pick glucose up via glucose transporters

step 1 from there: phosphorylation of glucose via HEXOKINASE or GLUCOKINASE

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2
Q

types of glucose transporters

A

active vs facilitated transport

insulin sensitive vs. insulin insensitive

active transport [Na-glucose cotransporters]

  • insulin-insensitive
    • intestinal epithelium
    • renal tubules
    • choroid plexus

facilitated transport [dependent on glucose conc gradient]

  • insulin-sensitive [GLUT4]
    • sk muscle, adipose tissue (“need insulin 4 GLUT4 in the 4 muscle/fat limbs”)
  • insulin-insensitive
    • most tissues [liver, brain, RBCs, etc]
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3
Q

GLUT4 mobilization

A

insulin dependent

muscles/adipose tissue

in absence of insulin, GLUT4 is sequestered intracellularly in vesicles

​1. insulin binds to cell membrane receptor, upregulates recruitment of GLUT4 to cell membrane

  1. GLUT4 increases insulin-mediated uptake of glucose into cell
    * glucose phosphorylated to keep it trapped in cell
  2. when insulin drops, GLUT4 moves back into intracellular storage pool for recycling
    * vesicles fuse to form endosome
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4
Q

key GLUT transporters

  • relative Km
  • site of action
A

GLUT1 : low Km (1)

  • basal glucose uptake in RBCs and brain

GLUT2 : high Km (15-20)

  • pancreatic beta cells (regulation of insulin)
  • liver (storage of excess glucose)

GLUT3 : low Km (1)

  • basal glucose uptake in brain neurons

GLUT4 : medium Km (5) - insulin dependent

  • sk muscle, adipose tissue
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5
Q

how does a cell hang on to glucose?

A

“tagging” with ATP makes glucose → glucose-6-phosphate

  • G6P v hydrophilic, won’t diffuse out of cell
  • catalyzed by glucokinase (liver) or hexokinase (all tissues)
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6
Q

hexokinase vs glucokinase

  • location
  • relative Km
  • inhibition
A

hexokinase (works at max levels even when glucose low)

  • all tissues
  • low Km
  • G6P feedback inhibition

glucokinase (stores continuously, but best when glucose is high - insulin dep)

  • liver
  • high Km
  • no feedback inhibition

implication: lowish Km of GLUT4 and low Km of hexokinase means muscle/fat are priority, but there is feedback inhibition to prevent them from trapping so much glucose that plasma stores drop

similarly, high Km of GLUT2 and high Km of glucokinase means liver only picks up glucose for storage when there’s enough to go around but lack of feedback inhibition means it can do this continuously (taking in more glucose over time)

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7
Q

de vivo disease

A

hereditary deficiency of GLUT1

  • drop in insulin-indep GLUT1 which picks up glucose in brain
    • decreased glucose in CSF

symptoms

  • seizures and devpt delay
  • neuro symptoms: ataxia, dystonia, dysarthia

tx

  • ketogenic diet (high protein/fat) - ketones provide alt energy source for brain in absence of glucose
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8
Q

glycolysis: two phases, three enzymes, net gains

A

two phases

  1. “preparation”

6-carbon glucose → 3-carbon glyceraldehyde-3-P

  1. “payoff”

G3P → pyruvate

three regulated enzymes (kinases)

  1. gluco/hexokinase
  2. phosphofructokinase-1 (PFK1)
  3. pyruvate kinase

net gains

  • 10 rxns that turn 6C glucose into 2 x 3C pyruvate
    • ​prep: 2ATP consumed
    • payoff: 4ATP + 2NADH produced
  • ​most rxns are reversible (except for the ones regulated by the three enzymes)
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9
Q

3 key regulated rxns of glycolysis

  • regulation by hormones
A

in general

  • insulin: upregulates glycolysis (fed state)
  • glycogen: downregulates glycolysis (fasted state)

glucokinase: glucose → G6P

PFK1: fructose-6P → fructose-1,6-bisphosphate

pyruvate kinase: phosphoenolpyruvate → pyruvate

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10
Q

regulation of hexokinase vs glucokinase

A

hexokinase

  • feedback inhibition by G6P

glucokinase

  • inhibited by F6P : gets GK transported into nucleus and sequestered there via binding to GKRP (GK reg protein)
    • inhibition reversed either by high intracell glucose or high intracell F1P
  • expression of GK increased by insulin
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11
Q

PFK1

A

regulates first committed step of glycolysis

fructose6P → fructose1,6bisP

  • allosteric enzyme : regulated by many factors

regulation differs in muscle and liver…

  • high glucose: lots of PFK1 activity in liver
  • energy demads: lots of PFK1 activity in muscle
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12
Q

allosteric regulation of PFK1

A

“high energy” molecules inhibit PFK1

  • ATP
  • citrate

“low energy” molecultes activate PFK1

  • AMP
  • fructose-2,6-bisphosphate also activates PFK1 [middleman for hormonal regulation]
    • F6P → F2,6BP via PFK2
      • PFK2 is upregulated by insulin via dephos, downregulated by glucagon via phos
    • F2,6BP activates PFK1 to keep glycolysis moving (F6P → F1,6BP via PFK1)
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13
Q

how do we achieve the differential regulation of PFK1 in muscle and liver tissue?

A

distinct PFK2 enzymes present in muscle and in liver

  • liver PFK2 follows regular hormonal reg (insulin upreg via dephos, glucagon downreg via phos)
  • muscle PFK2 dependent on allosteric reg by accumulated AMP during exercise
    • ensures that skeletal stores of ATP, glycogen will be replenished regardless of glucose status broadcasted by hormones
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14
Q

generation of NADH

A

occurs during conversion of glyceraldehyde3phosphate → 1,3bisphosphoclycerate [via glyceraldehyde3Pdehydrogenase]

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15
Q

energy generation through substrate level phosphorylation

A

substrate level phos = direct transfer of P from a substrate to ADP/GDP (as opposed to ATP gen via oxphos]

1,3BPG → 3PG + ATP [via phosphoglycerate kinase]

*can also happen through intermediate conversion to 2,3BPG [R-shifter of Hb dissociation curve!]

  • increased glycolysis increases 2,3BPG leading to increased O2 delivery to tissues!
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16
Q

energy generation via pyruvate formation

A

phosphoenolpyruvate → pyruvate + ATP [via pyruvate kinase]

  • second instance of substrate-level phosphorylation in glycolysis
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17
Q

regulation of pyruvate kinase

A

allosteric regulation

  • feed forward activation by fructose 1,6-bisphosphate

hormonal regulation

  • insulin upreg
  • glucagon downreg
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18
Q

fates of pyruvate

A

cells w mitochondria and O2?

TCA cycle, ATP gen

cells without mitochondria or lacking O2?

lactate gen, regen of NAD+

  • allows another round of glycolysis and gen of 2ATP
  • can lead to transient lactic acidosis
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19
Q

anaerobic glycolysis

A

lactate formation

  • major fate of pyruvate in tissues lacking mito or w lousy vasc (lens/cornea of eye, kidney medulla, RBCs)

in exercising muscle: conversion of pyruvate → lactate

  • allows glycolysis to continue by recycling NADH → NAD

in liver, heart: NADH is low

  • so lactate → pyruvate, NAD → NADH
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20
Q

MODY

A

maturity-onset diabetes of young

monogenic - traceable to individ mutation

  • auto dominant disorder : mutations of glucokinase cause 10-65% MODY
  • mild diabetes, only rarely complicated, often treated with meal planning only
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21
Q

pyruvate kinase deficiency

A
  • second most common cause of hemolytic anemia

RBCs lack mitochondria → are completely dep on glucose and glycolysis for egy needs

  • use glucose to maintain Na/K ATPase → keeps osmotic balace which keeps cell from swelling/lysing → hemolytic anemia
  • before lysis, see distorted cell membranes - characteristic spiculated appearance
  • decrease in RBCs = decrease in O2 delivery = buildup of glycolytic intermeds like 2,3BPG
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22
Q

causes of 2,3BPG buildup

consequence

A

2,3BPG causes O2 diss curve to shift RIGHT

  • better delivery of O2 to tissues

causes

  • decreased RBC count (hemolytic anemia)
  • smoking (compensates somewhat for decreased O2 due to CO)
  • altitude acclimatization
  • COPD
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23
Q

fluoride and glycolysis

A

fluoride and phosphate complex together, competitively inhibit enolase → stop glycolysis

[used to stabilize glucose in blood specimens]

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24
Q

TCA cycle overview

A

occurs in mitochondria, generates energy through oxidation of acetylCoA [derived from carbs, fats, proteins] → CO2 + H2O + ATP

essential/conserved (metabolic defects are v rare)

functions

  • generate free energy for ATP synthesis
    • fats, carbs, proteins are oxidized to CO2 → produce NADH and FADH2 for oxphos → ATP and H2O
  • interconversion of fuel ⇔ metabolites
    • first intermediate: acetyl CoA - pdt of many catabolic pathways
25
Q

energy yield of acetyl CoA

A

fats, carbs, amino acids are metabolized to acetyl CoA

each acetyl CoA yields:

  • 3 NADH (x3ATP)
  • 1 FADH2 (x2ATP)
  • 1 GTP (=1ATP)

1 acetyl CoA = 12 ATP

26
Q

anapleuritic reactions

A

rxns involving catabolism + anabolism

ex. TCA cycle

  • TCA cycle generates various intermediates for cellular metabolic pathways
    • i.e. it’s important to “refill” these intermediates so the cycle can run to completion
  • anapleuritic rxns “fill in” the TCA cycle

implication

  1. TCA intermediate levels rise and fall depending on needs of cell
  2. needs of cell will influence TCA cycle via shifts in intermediate pool levels
27
Q

TCA intermediates and fates

A

oxaloacetate: intermediate of gluconeogenesis

citrate, oxaloacetate, acetylCoA: membrane transport mechs

alpha ketoglutarate, oxaloacetate: transamination rxns

28
Q

pyruvate keys: aerobic fed conditions

A

aerobic fed conditions

  • pyruvate → acetyl CoA [pyruvate dehydrogenase complex]
  • pyruvate → alanine [pyridoxal phosphate-dependent alanine aminotransferase - remember B6!]
29
Q

pyruvate keys: aerobic fasting conditions

A

aerobic fasting conditions

  • pyruvate → oxaloacetate [biotin-dependent pyruvate carboxylase]
30
Q

pyruvate keys: anaerobic conditions

A

anaerobic conditions

  • pyruvate → lactate [lactate dehydrogenase]
  • in O2-deprived muscle: pyruvate → alanine [alanine aminotransferase]
31
Q

pyruvate dehydrogenase complex

A

bridge between carbs and TCA cycle

PDC converts pyruvate → acetyl CoA, which is used in TCA cycle

complex of 3 enzymes: E1, E2, E3

  • each is critical to complex fx
  • each has specific cofactors - deficiency of cofactor can produce pathology
32
Q

E1

A

pyruvate dehydrogenase component

24 chains

prosthetic: TPP

catalyzes: oxidative decarboxylation of pyruvate

33
Q

E2

A

dihydrolipoyl transacetylase

24 chains

prosthetic: lipoamide

catalyzes: transfer of acetyl group to CoA

34
Q

E3

A

dihydrolipoyl dehydrogenase

[also in alphaketoglutarate dehydrogenase complex and branched chain alpha-ketoacid dehydrogenase complex]

12 chains

prosthetic: FAD

catalyzes: regen of oxidized form of lipoamide

35
Q

req coenzymes for PDH complex activity

deficiency issues

A

B1 (thiamine) : thiamine pyrophosphate (TPP)

B5 (pantothenic acid) : CoA

lipoic acid

B2 (riboflavin) : flavin adenine dinucleotide (FAD)

B3 (niacin) : nicotinamide adenine dinucletide (NAD+)

4 vitamin derivatives + lipoic acid (made in sufficient amt in body)

  • deficiencies in any of the coenzymes affect ability to get egy from glucose → sk muscle weakness, neurological disease
36
Q

PDH complex enzyme cofactor requirements

A

E1 - thiamine pyrophosphate (B1 derivative)

E2 - CoA (B5 deriv), lipoic acid

  • resp for step producing CoA [i.e. need for CoA]

E3 - FAD (B2), NAD+ (B3)

37
Q

B1/thiamine deficiency

A

B1/thiamine is used by PDH, alphaketoglutarate DH, branched chain alphaketoacid DH, transketolase

  • deficiency affects nucleic acid synthesis, energy metabolism

syndromes

  • beri beri
    • US: most common in alcoholics (poor nutrition, affects of excess alc on ability to absorb/store thiamine)
    • dry (muscle wasting, neuropathy) and wet (CHF + edema)
  • Wernicke’s encephalopathy
    • triad of confusion, opthalmoplegia, ataxia
  • Korsakoff’s psychosis
    • memory loss, confabulation, personality change
38
Q

affects of arsenite and mercury

A
  • inhibit enzymes that use lipoic acid as a cofactor (including PDH complex)
  • CNS pathologies (ex. “mad as a hatter”!)
  • tx: BAL (British anti-Lewisite) - heavy metal chelator
39
Q

arsenic poisoning

A

tasteless, odorless white powder

affects E2 subunit of PDH complex (and other enzymes using lipoic acid as coenzyme)

signs

  • PDC deficiency (lactic acidosis, neuro disturbances)
  • garlic breath, “rice-water” stools that are bloody, vomiting

fun fact: Van Gogh’s emerald green paint had As might have contributed to his mental episodes

40
Q

allosteric regulation of PDH complex

A

high energy moleculte inhibit PDH

  • ATP
  • acetyl CoA
  • NADH
41
Q

covalent modification : regulation of PDH complex

A

PDH kinase phosphorylates PDH → inactivates PDH

  • activated by high energy molecules

PDH phosphatase dephosphorylates PDH → activates PDH

  • activated by insulin in adipose tissue
  • activated by Ca in muscle tissue
42
Q

dichloroacetic acid

A

synthetic analog of pyruvate

  • can bind to PDH kinase, inhibiting its action
    • prevents inhibition of PDH by keeping it in active dephos form

*might be effective treatment for lactic acidosis or MELAS, but clinical trials havent shown it

43
Q

regulation of PDH complex

A

allosteric

  • high energy mols inhibit

covalent

  • dephosphorylation (PDH phosphatase) activates
  • phosphorylation (PDH kinase) inhibits
  • high energy mols inhibits
44
Q

PDH complex deficiency

A
  • metabolic and neurologic defects
    • delayed devpt and reduced muscle tone
    • often associated with ataxia and seizures
    • some have congenital malformation of brain
  • most commonly due to mutation in X-linked E1 gene

will see accumulation of pyruvate and lactate, but normal pyruvate : lactate ratio

  • glycolysis occurs, but can’t do anything with the pyruvate except reduce it into lactate

tx

  • ketogenic diet, severe restriction of protein and carb : improved mental devpt
    • ensures that cells use acetyl CoA from fat metabolism
  • if mutation affects binding of thiamine to E1, might try high dose thiamine supplementation
45
Q

metabolic and neurologic conseqs of PDH compex deficiency

A

metabolic : lactic acidosis (pyruvate → lactate)

neurological : hypotonia, poor feeding, lethargy, seizures, mental retardation

46
Q

3 enzymes sharing E3…

A
  1. PDH complex
  2. alpha ketoglutarate DH
  3. branched chain alpha ketoacid DH
47
Q

Leigh disease

A

group of disorders characterized by lactic acidosis (rare)

  • defects in PDH and alpha ketoglutarate complexes → cant catabolize BCAAs
    • incrased levels of lactate, alpha ketoglutarate, BCAAs
  • tissues dependent on aerobic metabolism (brain, muscle) most severely affected
    • impaired motor fx, neuro dorders, mental retardation
48
Q

TCA cycle overview

A
  • occurs in mitochondria
    • all organs except ones without mito go through it
  • runs during fasted and fed states
  • aerobic
  • step 1: condensation of acetyl CoA + OAA → citrate
    • OAA regenerated at end of cycle
  • produces 3NADH + 1FADH2 + GTP + CO2
49
Q

irreversible reaction of TCA cycle and enzymes/regulation

A
  1. acetyle CoA → citrate
    * citrate synthase
  2. isocitrate → alpha ketoglutarate
    * isoditrate dehydrogenase
  3. alpha ketoglutarate → succinyl CoA
    * alpha ketoglutarate dehydrogenase

regulation via allosteric activation/inhibition [NOT HORMONES]

  • HIGH ENERGY mols DEACTIVATE : ATP, NADH
  • LOW ENERGY mols ACTIVATE: ADP, CA
50
Q

role of cellular energy in determining TCA cycle rate

A

high cellular energy → TCA cycle inhibited

low cellular energy → TCA cycle activated

51
Q

allosteric regulation of TCA cycle

A

ATP, NADH, succinyl CoA, fatty acyl derivatives all indicate high energy

  • inhibit TCA cycle

ADP indicates low energy

  • activates TCA cycle
52
Q

“Citrate Is Krebs’ Starting Substrae For Making OAA”

A

stops on the TCA cycle

  • citrate
  • isocitrate
  • alphaKetoglutarate
  • succinyl CoA
  • succinate
  • fumarate
  • malate
  • oxaloacetate
53
Q

oxidative decarboxylation in TCA cycle

A

2 successive decarboxylations via 2 dehydrogenase rxns → release of 2 CO2 + 2 NADH

  • isocitrate dehydrogenase
  • alpha ketoglutarate dehydrogenase
54
Q

substrate level phos in TCA cycle

A

succinyl CoA → succinate

[succinyl CoA thiokinase - takes off the CoA, generates a GTP)

  • substrate level phos producing a GTP
55
Q

3 reversible rxns to wind up TCA cycle

A

succinate → fumarate

[succinate dehydrogenase - FAD reduced to FADH2 (complex II of etc)]

fumarate → malate

[fumarase - adds a H2O]

malate → oxaloacetate

[malate dehydrogenase - completes recycling process, generates NADH]

56
Q

net carbon yield of TCA cycle

A

ZERO

  • 2 C introduced as acetyl CoA
  • 2 C liberated as CO2

implication: need to provide the other intermediates of the cycle in order for rxn to proceed

  • constant input of acetyl CoA would keep the cycle running smooth forever
  • TCA cycle doesn’t operate in isolation…
    • intermediates are pulled off in other direction/rxns, need to be replaced via anapleuritic rxns [involve intermediates]
57
Q

energy yield from TCA cycle

A

3 NADH [NADH → NAD = 3ATP]

1 FADH2 [FADH2 → FAD = 2ATP]

1 GTP [= 1ATP]

12 ATP total

58
Q

net energy production from aerobic resp

A

1 glucose

glycolysis: 2 ATP, 2 NADH

  • each NADH from glycolysis worth either 2 or 3 ATP depending on the transporter used to shuttle it to mito

2 pyruvate

TCA cycle: 2 GTPv, 6 NADH, 2 FADH2

38 ATP total

Gastrointestinal System (35 decks)

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